Peroxisome proliferators-activated receptor (PPAR) is a ligand-dependent transcription factor belonging to a nuclear receptor super-family likewise steroid receptors, retinoid receptors, thyroid receptors and the like. The receptor includes three isoforms (type α, type γ and type δ (or type β)), which have been identified in various animal species (Non-patent document 1). Among these, PPARα distributes in liver, kidney or the like having high fatty acid catabolic ability (Non-patent document 2), and positively or negatively controls expression of genes involved in fatty acid metabolism or intracellular transport (for example, acyl CoA synthetase, fatty acid binding protein or lipoprotein lipase) and genes of apolipoproteins (AI, AII, CIII) involved in metabolism of cholesterol and neutral lipid. PPARγ is highly expressed in adipocyte, and involved in differentiation of adipocyte (Non-patent document 3). PPARδ is universally expressed in biological tissues, mainly in nerve cells.
As to physiological significance of PPARδ, involvement in fatty acid burning is recently reported (Non-patent documents 4 and 7), however, there still remain a lot of unclear points. In this manner, each isoform of PPAR plays a specific role in a specific organ or tissue.
Furthermore, it is also reported that PPARα-knockout mouse exhibits hypertriglycemia with age, and gets obesity which is mainly associated with increase in white adipocyte (Non-patent document 5). This strongly suggests the relation between activation of PPARα and blood lipid (cholesterol and neutral lipid) lowering activity.
On the other hand, as antihyperlipidemic drugs that are dominantly used at the present day, statin drugs and fibrate drugs are known. Statin drugs, however, are poor in free fatty acid and triglyceride lowering ability, and fibrate drugs are poor in cholesterol lowering ability. As to fibrate drugs, various side effects that are attributable to exhibition of wide pharmacological property, such as gastrointestinal damages, eruption, headache, hepatic function disorder, renal function impairment, gallstone have been reported, and hence there is need for development of an antihyperlipidemic drug based on a specific mechanism that will not cause such side effects.
In consideration of the current cases of conventional antihyperlipidemic drugs and relationship between the role regarding lipid metabolism control function of transcription factor called PPARα, and clinical condition of hyperlipemia that has been revealed heretofore, creation of a compound that directly binds as a ligand to PPARα, in particular, to human PPARα and is able to potently activate human PPARα may provide a therapeutic agent exhibiting blood lipid (both cholesterol and neutral lipid) lowering activity according to an extremely specific mechanism.
As an endogenous ligand against PPARα, eicosanoid of hydroxyeicosatetraenoic acid (HETE) group generated through oxidation by cytochrome P-450, in particular 8-HETE, 8-HEPE and the like are reported as well as LTB4 which is a metabolite of arachidonic acid (Non-patent document 6). These endogenous unsaturated fatty acid derivatives are instable in both metabolic and chemical aspects, so that they cannot be provided as pharmaceuticals.
On the other hand, as a compound which is reported to have PPARα agonist activity, compounds of the formulas (A) to (J) listed in Table 1 are known, however, none of these include compounds having a benzoic acid structure substituted with alicyclic amino group, and hence they differ in structure from compounds of the present invention.
TABLE 1PatentDocumentFormula 1  2  3  4  5  6  7  8  9 10
Furthermore, as a compound having a similar structure to compounds of the present invention and reported for PPARγ agonist activity, Patent document 11 discloses a compound represented by the general formula (K)
[wherein R1 represents the general formula (K-a)
or general formula (K-b)
(wherein R5 represents a hydroxyl group, or C1-C9 alkoxy group, and R6 represents a C1-C6 alkyl group or the like); R2 and R3 represent a hydrogen atom, alkyl group or the like; X represents —CH2—NR8CO—, —N(R8)—COCH2— or the like; R4 represents a phenyl group, benzyl group or the like; R8 represents a hydrogen atom or C1-C6 alkyl group] (explanation for substituents is partly extracted), however this compound is a biphenyl alkanoic acid derivative, and is different in structure from compounds in accordance with the present invention.
Furthermore, as a compound having a similar structure to compounds in accordance with the present invention, and reported to have PPAR agonist activity, Patent document 12 discloses a compound represented by the general formula (L)
[wherein L represents a single bond, or a C1-C6 alkylene group which may have one or more substituents or the like; M represents a single bond, or a C1-C6 alkylene group which may have one or more substituents or the like; T represents a single bond or the like; W represents carboxyl group;- - - -   [Chemical formula 5]represents a single bond or a double bond; X represents a single bond, an oxygen atom or the like; Y represents a 5 to 14-membered aromatic group which may have one or more substituents and one or more hetero atoms, or a C3-C7 alicyclic hydrocarbon group; rings Z and U represent 5 to 14-membered aromatic groups which may be identical or different, and may have one to four substituents, and one or more hetero atoms, and may be saturated in a part of the ring] (explanation for substituents is partly extracted). As a compound that is reported as a PPAR receptor ligand, Patent document 13 discloses a compound represented by the general formula (M)
[wherein ring ArI, ring ARII, and ring ARIII independently represent an aryl, heteroaryl or the like; A represents an oxygen atom, sulfur atom or the like; B represents an oxygen atom, sulfur atom, a single bond or the like; D represents an oxygen atom, sulfur atom, single bond or the like; E represents a single bond or ethylene group; a, b, c and e represent 0 to 4; d represents 0 to 5; f represents 0 to 6, R1, R3, R5, R7, R9 and R11 independently represent a hydrogen atom, halogen atom or the like;
R2, R4, R6, R8, R10 and R12 independently represent —(CH2)q—X; q represents 0 to 3, X represents a hydrogen atom, halogen atom or the like; Z represents R2102C—, R21CO— and the like; R21 represents a hydrogen or the like] (explanation for substituents is partly extracted). However, ring Z or ring ArII of these compounds (Patent documents 12 and 13) does not contain an alicyclic amino group which is characteristic of compounds in accordance with the present invention, and differs in structure from compounds in accordance with the present invention.
Furthermore, as a compound having a similar structure to compounds in accordance with the present invention and reported to have PPAR agonist activity, Patent document 14 discloses a compound represented by the general formula (N)
[wherein ring A represents a C3-C8 cycloalkyl which may contain an oxygen atom, or C3-C8 cycloalkenyl which may contain an oxygen atom; R1, R2, R4 and R5 represent a hydrogen atom, fluorine atom, chlorine atom, bromine atom, hydroxyl group, nitro group, trifluoromethyl group, trifluoromethoxy group, C1-C6 alkyl group, or C1-C6 alkoxy group; R3 represents a hydrogen atom, or C1-C6 alkyl group; and X, Y represent a C1-C6 alkylene which may be substituted with an oxygen atom]. However, ring A does not contain an alicyclic amino group which is characteristic of compounds in accordance with the present invention, and ring A and the benzoic acid moiety are bound via Y, so that it is different in structure from compounds in accordance with the present invention.
Furthermore, as a compound having a similar structure to compounds in accordance with the present invention and reported to have triglyceride and cholesterol lowering activity, Patent documents 15 to 19 disclose a compound represented by the general formula (O)
[wherein Z represents an oxygen atom or sulfur atom; X represents a hydrogen atom, halogen atom, lower alkyl group, carboxyl group, lower alkoxycarbonyl group or the like; Y represents a hydrogen atom, halogen atom, lower alkyl group when Z is a sulfur atom, and represents a hydrogen atom, halogen atom, lower alkyl group, lower alkoxy group or the like when Z is an oxygen atom] (explanation for substituents is partly extracted). However, this compound is a derivative of morpholin one which is different from an alicyclic amino group which is characteristic of compounds in accordance with the present invention, and has a different structure from compounds in accordance with the present invention because only para-substituted benzoic acid derivative (X═COOR) is described in Examples of the patent documents. Furthermore, the patent documents include no report about PPARα agonist activity.
As a compound having a cyclic amino benzoic acid structure, Patent document 20 discloses as a compound having integrin antagonist activity, a compound represented by the general formula (P)
[wherein R1 represents a hydrogen atom, hydroxyl group or the like; R2 represents a hydrogen atom or halogen atom, or R1 and R2 together represent a 4 to 7-membered ring which may contain up to two oxygen atoms, nitrogen atoms, or sulfur atoms, and up to two double bonds; R3 represents a hydrogen atom, C1-C10 alkyl group or the like; R4 represents a hydrogen atom, halogen atom or the like; R5 represents a hydrogen atom, C1-C6 alkyl group or the like, or R3 and R5 together represent a 4 to 7-membered ring which may contain up to two oxygen atoms, nitrogen atoms, or sulfur atoms, or up to two double bonds; R6 represents a hydrogen atom, C1-C4 alkyl group or the like; R7 represents a hydrogen atom or C1-C4 alkyl group, or R3 and R7 bind to each other to represent a ring; X represents an oxygen atom or two hydrogen atoms] (explanation for substituents is partly extracted). However, for this compound, no report about PPARα agonist activity is found, and the compound is a benzoic acid derivative having a cyclic amino group at para position of carboxylic acid, and hence differs in structure from compounds in accordance with the present invention.
Furthermore, as a compound having a cyclic amino benzoic acid structure, Patent document 21 discloses a compound having serine protease inhibitory activity, a compound represented by the general formula (Q)
[wherein ring B represents a phenyl group or pyridyl group, W represents a C2-C10 alkyl group and the like; Z1 represents a 5 to 7-membered monocyclic or 8 to 11-membered bicyclic aryl group or the like; L represents —(R18R19)s—Y—(R18aR19a)t—; Y represents a carbonyl group or the like; R1 and R2 independently represent a hydrogen atom or the like, or R1 and R2 together represent a 5 to 7-membered saturated heterocycle which may be substituted with one or two R26; R5 and R6 independently represent a hydrogen atom or the like; R7 represents a hydrogen atom, halogen atom or the like; R8 represents a hydrogen atom, alkyl group or the like; R18, R18a, R19, and R19a represent a hydrogen atom, lower alkyl group or the like; R26 and R27 represent a hydrogen atom, alkyl group or the like; m represents 0, 1, or 2 when ring B is phenyl, or represents 0 or 1 when B is pyridyl; s, t independently represent 0, 1 or 2] (explanation for substituents is partly extracted). However, for this compound, no report about PPARα agonist activity is found. Furthermore, this compound is an amidine derivative, and differs in structure from compounds in accordance with the present invention in that the rings B and L to be substituted adjacently bind to the ring formed by R1 and R2.
As a compound having cyclic amino benzoic acid structure, Patent document 22 discloses as a compound having factor Xa inhibitory activity, a compound represented by the general formula (R)[Chemical formula 11]R0-Q-X-Q′-W-U-V-G-M  (R)[wherein R0 represents aryl group or the like which may be substituted with R2; Q, Q′ represent a bonding hand, carbonyl or the like; X represents a bonding hand, 3 to 7-membered heteroaryl group or the like; W represents a 5 to 14-membered aryl group which may be substituted with R1, 5 to 14-membered heteroaryl group which may be substituted with R1 or the like; U and G represent a bonding hand, —(CH2)m—, —(CH2)m—O—(CH2)m— or the like; V represents 3 to 7-membered cycle which may contain 1 to 4 oxygen atoms, nitrogen atom, and sulfur atom, and may be substituted with R14, bonding hand, or the like; M represents a 6 to 14-membered aryl group which may be substituted with R14, hydrogen atom or the like; R1 represents a halogen atom, nitro group or the like; R2 represents a halogen, nitro group or the like; R14 represents a halogen atom, OH, COOH or the like] (explanation for substituents is partly extracted), and Patent document 23 discloses a compound represented by the general formula (S)
[wherein R1, R2 and R3 which are identical or different, represent a hydrogen atom, hydroxyl group or the like; and R represents the general formula (S-a)
(wherein R7 represents a hydrogen atom, lower alkyl group, or —C(═R9)R10; R8 represents hydrogen atom, lower alkyl group or the like; Y1 represents an oxygen atom, —CONH— or the like; Y2 represents an oxygen atom, sulfur atom, or a single bond; Y3 represents a single bond,
Y4 represents an oxygen atom, a single bond or the like, Y5 represents —(CH2)p—, a single bond or the like; A represents
m and n which are identical or different, each represents 0 or an integer from 1 to 3; s, t which are identical or different, each represent an integer from 1 to 3; R9 represents an oxygen atom, sulfur atom or the like; R10 represents a lower alkyl, lower alkoxy group; R14 represents a carboxyl group or the like) and so on] (explanation for substituents is partly extracted). However, as to the compound described in Patent document 22, no report about PPARα agonist activity is found. Furthermore, all the benzoic acid derivatives substituted with a cyclic amino group that are described in examples in patent specification are compounds in which 4-position of benzoic acid is substituted with an alicyclic amino group and hence are different from compounds in accordance with the present invention. Furthermore, as to the compound in Patent document 23, no report about PPARα agonist activity is found, and examples of the patent specification lack description on benzoic acid derivative substituted with an alicyclic amino group.
As a compound having a similar structure to compounds in accordance with the present invention, compounds shown by formulas (T) to (AA) in Table 2 having histone deacetylation inhibitory activity [in general formulas (T) to (AA), R1 represents —CONR8R9 (wherein R8 and R9 each independently represent a hydrogen atom, hydroxyl group, C1-6 alkyl group or the like), NHCOR10 (wherein R10 represents a hydrogen atom, C1-6 alkyl group or the like) or the like, and in general formulas (T) to (Y), R2 represents a hydrogen atom, halogen atom, hydroxyl group or the like] (explanation for substituents is partly extracted) are known. However, no reports about PPARα agonist activity are found for these compounds. In these compounds, the substituent R1 is a functional group such as amide or hydroxamic acid, and a carboxyl group and a lower alkoxycarbonyl group which provide structural feature of the present invention are not contained. Therefore, these compounds are different in structure from compounds in accordance with the present invention. Furthermore, in examples of patent specifications of Patent documents 24 to 29, benzoic acid derivatives substituted with a cyclic amino group are described as intermediates, however, these compounds are also different in structure from compounds in accordance with the present invention because the cyclic amino group being bound thereto is 1-piperadyl group, 4-aminopiperidino group or the like, and no report about PPARα agonist activity is found. Furthermore, examples in patent specifications of Patent documents 30 and 31 completely lack description about benzoic acid derivatives.
TABLE 2Patent DocumentFormula24 25 26 27 28 29 30 31
Furthermore, as a compound having a similar structure to compounds in accordance with the present invention, compounds shown by formulas (AB) to (AD) listed in Table 3 are known as a compound having integrin αvβ3 antagonist activity. In any of these compounds, however, a carboxyl group binds to a benzene ring via a linker, and no report about PPARα agonist activity is found. Although benzoic acid derivatives substituted with an alicyclic amino group are described as intermediates in examples of the patent specifications, no report about PPARα agonist activity is found for these compounds.
TABLE 3PatentDocumentFormula32 33 34
Furthermore, as a compound having a similar structure to compounds in accordance with the present invention, Patent document 35 discloses a compound represented by the general formula (AE) as an inhibitory agent of Na+/H+ alternate transport function:
[wherein R1 and R2 each independently represent a hydrogen atom, C1-C6 alkyl group, Ph, PhCO or the like; R3 and R4 each independently represent a hydrogen atom, C1-C6 alkyl group or the like] (explanation for substituents is partly extracted). However, no report about PPARα agonist activity is found for these compounds. Furthermore, this compound is characterized by a benzoyl guanidine structure, and is different in structure from compounds in accordance with the present invention in that the cyclic amino group that is to bind to a phenyl group is 4-aminopiperidino group. Furthermore, in examples of the patent specification, benzoic acid derivatives substituted with a cyclic amino group are described as intermediates, however, these compounds are also different in structure from compounds in accordance with the present invention, and no report about PPARα agonist activity is found. Furthermore, as a compound having a similar structure to compounds in accordance with the present invention and reported to be a PPAR receptor ligand, Patent document 36 discloses compound represented by the general formula (AF)
[wherein ring ArI and ring ARII independently represent an aryl, heteroaryl or the like, A represents an oxygen atom, sulfur atom, compound represented by the general formula (AF-a)
(wherein h represents 1 to 4; R14, R15 and R16 represent a hydrogen atom, alkyl group or the like, or R14 and R15 represent, together with nitrogen atom, 5-membered or 6-membered hetero cycle or the like) or the like, B represents an oxygen atom, sulfur atom or the like, E represents a single bond or an ethylene group, a and d represent 0 to 6, b and c represent 0 to 4, R1, R3, R5 and R7 independently represent a hydrogen atom, halogen atom or the like, R2, R4, R6, and R8 and R12 independently represent —(CH2)q—X, q represents 0 to 3, X represents a hydrogen atom, halogen atom or the like, Z represents R2102C—, R21CO— or the like, and R21 represents a hydrogen or the like] (explanation for substituents is partly extracted). However, in this compound, the cyclic amino group represented by the general formula (AF-a) binds to ring ArII via a linker, so that it is different in structure from compounds in accordance with the present invention. Furthermore, examples in patent specification lack description on a compound having a cyclic amino group. Furthermore, as a compound having a similar structure to compound of the present invention and reported to have PPARα agonist activity, Patent document 37 discloses a compound represented by the general formula (AG)
[wherein Y and V represent methylene or carbonyl group; F and G represent a hydrogen atom, halogen atom or the like; X represents Z or —B—C(R1R2)—Z; B represents an oxygen atom, sulfur atom or the like; Z represents —C(O)OH, —C(O)O—(C1-C6) alkyl or the like; R1 represents a hydrogen atom, (C1-C6)alkyl group or the like; R2 represents a hydrogen atom, (C3-C6) cycloalkyl group or the like; E represents a carbonyl group, sulfonyl group, methylene; W represents a bonding hand, carbonyl group, —N(H)— or the like; and A represents a mono-N— or di-N,N—(C1-C6)alkyl amino group, (C2-C6) alkanoyl amino group, partly or fully saturated or fully unsaturated 3 to 8-membered ring which may have 1 to 4 oxygen atom, sulfur atom, or nitrogen atom] (explanation for substituents is partly extracted). However, this compound is featured in that the ring J binds at a position other than nitrogen atom of the alicyclic amino group containing Y and V, and excludes compounds having the feature of compounds in accordance with the present invention that benzoic acid binds to a nitrogen atom of the alicyclic amino group, and hence is different in structure from compounds in accordance with the present invention. Furthermore, as a compound having a similar structure to compounds in accordance with the present invention and reported to have lipid lowering activity, Patent document 38 discloses a compound represented by the general formula (AH)
[wherein Ar represents a naphthyl group, pyridyl group or the like; X represents —CO—, or —SO2—, Y represents
Q represents —O— or a single bond; Z represents a 1 to 3 alkylene group or —CR5R6— (wherein R5 and R6 represent an alkyl group); R4 represents a hydroxyl group or —NH(CH2)mCOOH (wherein m represents a number from 1 to 3)] (explanation for substituents is partly extracted), and Patent document 39 discloses a compound represented by the general formula (AI)
[wherein Ar represents a naphthyl group, pyridyl group or the like; Y represents
Q represents —O— or a single bond, Z represents a 1 to 3 alkylene group or —CR5R6— (wherein R5 and R6 represent an alkyl group), R4 represents a hydroxyl group or —NH(CH2)mCOOH (wherein m represents a number from 1 to 3)] (explanation for substituents is partly extracted). In these compounds, however, substituent Ar—X or Ar—CO— binds to 4-position nitrogen atom of ring Y with respect to the phenyl group, and the substituted COR4 of these compounds binds to phenyl group via -Q-Z—, so that they do not include a benzoic acid derivative and are different in structure from compounds in accordance with the present invention. Furthermore, for these compounds, no report about PPARα agonist activity is found.
As a compound having a cyclic amino benzoic acid structure, Patent document 40 discloses, as a compound having serine protease inhibitory activity, a compound represented by the general formula (AJ)
[wherein ring B represents a phenyl group or pyridyl group; X2 represents N, CH or the like; W represents a C2-C10 alkyl group or the like; Z represents a 5 to 7-membered monocyclic or 8 to 11-membered bicyclic aryl group and the like; L represents —(R18R19)s—Y—(R18aR19a)t—; R1 and R2 independently represent a hydrogen atom or the like; R1 and R2 together represent an aromatic ring, heteroaromatic ring or the like; R8 represents a hydrogen atom or the like; R3 represents a hydrogen atom, alkyl group or the like; R18, R18a, R19 and R19a represent a hydrogen atom, lower alkyl group or the like; Y represents CO or the like; m represents 0, 1 or 2 when ring B is a phenyl, or represents 0 or 1 when ring B is a pyridyl; and s, t independently represent 0, 1 or 2] (explanation for substituents is partly extracted). For this compound, however, no report about PPARα agonist activity is found. Furthermore, it is different in structure from compounds in accordance with the present invention in that substituent rings B and L bind adjacently to the ring formed by the R1 and R2.
Furthermore, as a compound having a similar structure to the present invention, Patent document 41 discloses as a compound having p38MAP kinase inhibitory activity, a compound represented by the general formula (AK)
[wherein A ring represents a C5-C10 monocyclic, bicyclic hydrocarbon ring or the like; R1 represents COOR11, C1-C8 alkyl group, C2-C8 alkenyl group or the like; R2 represents a C1-C8 alkyl group; G and J each independently represent a carbon atom, nitrogen atom or the like; E represents a C1-C8 alkylene group, C2-C8 alkenylene group, —O— or the like; B ring represents a C5-C10 monocyclic, bicyclic hydrocarbon ring or the like; R3 represents a C1-C8 alkyl group, C2-C8 alkenyl group or the like; R11 represents a hydrogen atom, C1 to C8 alkyl group or the like; m represents 0 or integer from 1 to 5; n represents 0 or integer from 1 to 7; and 1 represents 0 or integer from 1 to 12,- - - -   [Chemical formula 26]represents a single bond or double bond] (explanation for substituents is partly extracted). However, this compound is a cyclic amide derivative which is different from the alicyclic amino group that is characteristic of compounds in accordance with the present invention, and all the benzoic acid derivatives that are described in examples of patent specification are para-substituted compounds and hence are different in structure from compounds in accordance with the present invention. Furthermore, no report about PPARα agonist activity is found.
Furthermore, as a compound having a similar structure to the present invention, Patent document 42 discloses as a compound having β3 adrenaline receptor agonist activity, a compound represented by the general formula (AL)
[wherein ring A represents an aromatic ring or hetero ring; X represents —OCH2—, —SCH2—, or bonding hand; T1 represents (CH2)m; T2 represents (CH2)n; T represents a bonding hand, C1-C6 alkyl group which may be substituted with substituent R11 or the like; R1, R2 and R3 each independently represent a hydrogen atom, C1 to 6 alkyl group or the like; R4 represents a hydrogen atom, C1 to 6 alkyl group or the like; R5 represents a COOR6, or a compound represented by the general formula (AL-a)
(wherein Y, Z each independently represent NR7, O or S; R6 represents a hydrogen atom, C1-C6 alkyl group which may be substituted with R11, R12 and R13, or the like; and a broken line represents a single bond or a double bond) or the like; m represents 1 to 3; n represents 1 to 3; R6 represents a hydrogen atom, alkyl group having 1 to 6 carbon(s) and the like; R11, R12, R13 each independently represent a C1-C6 alkyl group, halogen atom or the like] (explanation for substituents is partly extracted). However, this compound is featured by an amino ethanol structure, and the benzoic acid derivatives substituted with a cyclic amino group described in examples of patent specification are merely the compounds in which substitution with cyclic amino group occurs at para position of benzoic acid, and differ in structure from compounds in accordance with the present invention. Furthermore, no report about PPARα agonist activity is found.
As a compound having a similar structure to the present invention, Patent document 43 discloses as a compound having calcium receptor antagonist activity, a compound represented by the general formula (AM)
[wherein m represents an integer from 0 to 2; n represents an integer from 1 to 3; X represents a cyano group, nitro group or the like; Y represents a chlorine atom, fluorine atom or the like; Q and Z independently represent a hydrogen atom, R1, SO2R1′, C(O)OR1″ or the like; A represents a phenyl group or naphthyl group which may be substituted with a hydroxyl group, halogen atom or the like; R1, R1′ and R1″ independently represent a hydrogen atom, C1-C4 alkyl group or the like] (explanation for substituents is partly extracted). However, no report about PPARα agonist activity of this compound is found. In examples of the patent specification, no description is found about a benzoic acid derivative substituted with a cyclic amino group.
As a compound having a similar structure to the present invention, Patent document 44 discloses as a compound having integrin inhibitory activity, a compound represented by the general formula (AN)[Chemical formula 30]U-V-A-(Alk)j-(CO—NH)h-(Alk)g-B  (AN)[wherein g, h and I each independently represent 0 or 1; Alk represents an alkylene; U represents an amidino group, guanidine group or -(G-Alk)k-C(Q)-N(R)R1 (wherein G represents a single bond, oxygen atom or the like, Q represents an oxygen atom, sulfur atom or the like, R represents a hydrogen atom, alkyl group or the like; R1 represents an alkyl group, aryl group or the like; k represents 0 or 1), V represents general formula (AN-a)
general formula (AN-b)
(wherein W1 represents an oxygen atom, sulfur atom or the like; W3, W4, W5 and W6 represent N or C—R4; W7 represents a nitrogen atom or the like; R4 represents a hydrogen atom, halogen atom or the like; R6 represents a hydrogen atom, halogen atom or the like); A represents general formula (AN-c)
general formula (AN-d)
(wherein X1 represents a nitrogen atom or C—H; X2 represents C—H; Y1 represents —C(O)—, —C(S)— or the like; Z2 represents an oxygen atom, sulfur atom or the like; n, m each independently represent 0, 1 or 2, and n+m=1, 2, 3 or 4; r represents 1 or 2; R8, R9, R10 and R11 each independently represent a hydrogen atom, alkyl group or the like), B represents general formula (AN-e)
(wherein R15 represents a hydrogen atom, alkyl group or the like; R17 represents a hydrogen atom, alkyl group, aryl group or the like; R16 and R18 each independently represent a hydrogen atom, or alkyl group; E represents a carboxyl group, amide group or the like)] (explanation for substituents is partly extracted). However, this compound is a cyclic amide derivative and the like which is different from an alicyclic amino group which is characteristic of compounds in accordance with the present invention, and substituent U is amidino group, guanidine group or the like functional group. Therefore, the above compound lacks a carboxyl group and a lower alkoxycarbonyl group which are structural features of the present invention, and hence differs in stricture from compounds in accordance with the present invention. Furthermore, no report about PPARα agonist activity is found.
Furthermore, as a compound having a similar structure to compounds in accordance with the present invention, Patent document 45 discloses as a compound having integrin αvβ3 antagonist activity, a compound represented by the general formula (AO)
[wherein Q represents general formula (AO-a)
(wherein R7 represents a hydrogen atom, C1-8 alkyl group or the like; R13 represents a hydrogen atom, C1-8 alkyl group or the like; R19 represents a hydrogen atom, C1-8 alkyl group or the like; X represents a halogen atom, cyano group or the like; p represents an integer from 0 to 4; t represents an integer from 0 to 5), E, G, L and M each independently represent a hydrogen atom, C1-8 alkyl group or the like, J represents a hydrogen atom, C1-8 alkyl group or the like, R1 represents a halogen atom, phenyl group which may be substituted with (CH2)0-4CO2R16 or the like; R2 represents a hydrogen atom, C1-8 alkyl group or the like; R3 and R6 each independently represent a hydrogen atom, C1-8 alkyl group or the like; R16 represents a hydrogen atom, C1-8 alkyl group or the like; m, n and p each independently represent an integer from 0 to 4; o represents an integer from 2 to 5] (explanation for substituents is partly extracted). However, this compound is featured in that an aminoalkyl amino group binds to a cyclic amino group; and any cyclic amino group that binds to a benzoic acid derivative described in examples of the patent specification is 4-aminopiperidino group, and hence is different in structure from compounds in accordance with the present invention. Furthermore, no report about PPARα agonist activity is found. As a compound having a similar structure to the present invention, Patent document 46 discloses as a compound having factor Xa inhibitory activity, a compound represented by the general formula (AP)[Chemical formula 38]A-Y-D-E-G-J-Z-L  (AP)[wherein A represents a phenyl group, C1-C6 alkyl group, or C3-C8 cycloalkyl group which may be substituted with 0 to 2 R1 or the like; Y represents a bonding hand, —C(═O)— or the like; D represents a bonding hand, phenyl group substituted with 0 to 2 R1a or the like; E represents —N(R5)—C(═O)—, —C(═O)—N(R5)— or the like; G represents a bonding hand, —CR7R8— or the like; J represents general formula (AP-a)
(wherein R11, R11a and R11b independently represent a hydrogen atom, hydroxyl group or the like) or the like, Z represents a phenyl substituted with 0 to 2 R1b, naphthyl group substituted with 0 to 2 R1b or the like; L represents a hydrogen atom, cyano group, C(═O)NR12R13, C(═NR12)NR12R13 or the like; R1 represents a halogen atom, C1-4 alkyl group or the like; R1a represents a halogen atom, C1-4 alkyl group or the like; R1b represents a halogen atom, —OCH2-COOR2b or the like; R2b represents a hydrogen atom, C1-4 alkyl group or the like; R12 and R13 independently represent a hydrogen atom, C1-4 alkyl group or the like] (explanation for substituents is partly extracted). This compound dose not include benzoic acid derivatives which are substituted with a cyclic amino group, and differs in structure from compounds in accordance with the present invention. Furthermore, no report about PPARα agonist activity is found.    [Patent document 1] WO00/23407 pamphlet    [Patent document 2] WO00/75103 pamphlet    [Patent document 3] WO01/40207 pamphlet    [Patent document 4] WO02/38553 pamphlet    [Patent document 5] WO02/28821 pamphlet    [Patent document 6] WO02/064549 pamphlet    [Patent document 7] WO03/051821 pamphlet    [Patent document 8] WO03/059875 pamphlet    [Patent document 9] WO2004/010936 pamphlet    [Patent document 10] WO2004/010992 pamphlet    [Patent document 11] WO03/055867 pamphlet    [Patent document 12] WO02/098840 pamphlet    [Patent document 13] WO00/64876 pamphlet    [Patent document 14] WO03/020269 pamphlet    [Patent document 15] Japanese Patent Laid-Open Publication No. Sho 52-83676    [Patent document 16] Japanese Patent Laid-Open Publication No. Sho 51-149234    [Patent document 17] Japanese Patent Laid-Open Publication No. Sho 51-149235    [Patent document 18] Japanese Patent Laid-Open Publication No. Sho 51-146478    [Patent document 19] Japanese Patent Laid-Open Publication No. Sho 51-146479    [Patent document 20] WO03/030889 pamphlet    [Patent document 21] WO02/37937 pamphlet    [Patent document 22] WO02/051831 pamphlet    [Patent document 23] Japanese Patent Laid-Open Publication No. 2000-136190    [Patent document 24] WO03/075929 pamphlet    [Patent document 25] WO03/076395 pamphlet    [Patent document 26] WO03/076400 pamphlet    [Patent document 27] WO03/076401 pamphlet    [Patent document 28] WO03/076421 pamphlet    [Patent document 29] WO03/076422 pamphlet    [Patent document 30] WO03/076430 pamphlet    [Patent document 31] WO03/076438 pamphlet    [Patent document 32] WO01/54726 pamphlet    [Patent document 33] WO01/27090 pamphlet    [Patent document 34] WO01/27082 pamphlet    [Patent document 35] Japanese Patent Laid-Open Publication No. Hei 7-267926    [Patent document 36] WO00/64888 pamphlet    [Patent document 37] WO2004/048334 pamphlet    [Patent document 38] WO93/12086 pamphlet    [Patent document 39] EP0607536 pamphlet    [Patent document 40] WO02/42273 pamphlet    [Patent document 41] WO03/043988 pamphlet    [Patent document 42] WO02/06232 pamphlet    [Patent document 43] WO00/09132 pamphlet    [Patent document 44] WO01/44230 pamphlet    [Patent document 45] WO98/57638 pamphlet    [Patent document 46] WO00/71515 pamphlet    [Non-patent document 1] Proc. Natl. Acad. Sci., 1992, 89, 4653    [Non-patent document 2] Endocrinology, 1996, 137, 354    [Non-patent document 3] J. Lipid. Res., 1996, 37, 907    [Non-patent document 4] Nat. Med., 1998, 4, 1046    [Non-patent document 5] J. Biol. Chem., 1998, 273, 29577    [Non-patent document 6] Proc. Natl. Acad. Sci., 1997, 94, 4312    [Non-patent document 7] Cell, 2003, 113, 159